Benzo-c-phenanthridine alkaloids can be extracted from plants of the families Papaveracease, Fumariaceae, and Berberidaceae. Some of the palnts of these familes include Sanquinaria canadensis, Macleaya cordata, Bocconia frutescens, Carydalis sevctcozii, C. ledebouni, Argemone mexicanus, and Chelidonium majus. Among the most important benzo-c-phenanthridine alkaloids obtained from these plants are sanguinarine, chelirubine, macarpine, allocryptopine, protopine, hemochelidonene, sanquilatine, sanguirubine, and chelerythrine.
The best known of these alkaloids is sanguinarine, which has been extracted from the Sanguinaria canadensis plant (otherwise known as bloodroot, teterwort, redroot, puccoon, etc) a perennial heb native to North America. The sanguinaria plant and its juices have been used for various purpsoes in pre-historic and historic times. The plants have been used, in particular, as a fold remedies. The plants have generally been used whole, either undried (fresh) or dired, and the usual procedure is to powder the dried plant and mix it with a carrier. This folk remedy has been tried for such conditions as asthma, bronchitis, dysentary, ringworm, and a substantial list of other ailments.
The pure chemicals sanguinarine, chelerythrine, protopine, chelerubine, berberine, chelilutine, sanguilatine, macarpine, sanguirubine, and allocryptopine can be isolated from lants other than Sanguinaria. They are also available, although rarely, from some chemical supply houses. Semi-purified forms of the alkaloids are commercially available, and these are generally referred to as sanguinarine nitrate and sanguinarine sulfate. These "salts" are the salts of the mixed alkaloids of the plant Sanguinaria: mainly sanguinarine, chelerythrine, and protopine. While few references can be found in the literature regarding the usage of any of the pure benzophenanthridine alkaloids, plants containing such compounds have been used for a wide variety of medical ailments.
The alkaloid sanguinarine in solution has been shown to have some antifungal and antiprotozoan properties. The sanguinarine is applied as an emulsion topically to fungal infections. The antibacterial activity of sanguinarine has been found to vary with the attached radicals, and various salts of sanguinarine have been shown to have some activity. The hydrochloride and the sulfate salts have been found to have some activity against certain bacteria at certain concentrations. Sanguinarine nitrate is reported to have some bacteriostatic action against various types of bacteria.
The use of an extract of Sanguinaria canadensis as an ingredient in oral cleansing preparations, in particular, toothpaste, is disclosed in U.S. Pat. No. 4,145,412.
This extract is produced by treating a finely cut or ground bloodroot with an organic solvent, such as methanol. The bloodroot is thoroughly stirred with several volumes of the solvent, and is maintained in the solvent for 24 hours or more, at a temperature of about 60.degree. C. Subsequently, the solution is filtered and the methanol is evaporated. The residue is dissolved in chloroform, treated with concentrated hydrochloric acid, filtered and then dried. This dried extract is generally taken up in warm glycerine (65.degree. C.) for mixing with a carrier.
The extract is an excellent breath freshener, tissue conditioner and tooth cleansing agent.
Sanguinarine, a component of sanguinaria extract has also been used as an antiplaque agent and has been demonstrated to be effective in the prevention and control of plaque in U.S. Pat. Appln. Ser. No. 767,606, filed Aug. 20, 1985 now U.S. Pat. No. 4,683,133 which issued July 28, 1987.
However, in mammals with advanced periodontal disease, which is characterized by tissue destruction, high levels of collagenase activity, and alveolar bone resorption, there is a need to provide effective means to control and reverse these conditions.
Periodontal disease accounts for more than 50% of the total tooth mortality in the United States and is the leading threat to oral health in the world, and while limited advances have been made in both prevention and treatment, the essential pathogenesis of the disease is not well understood. Researchers do not doubt that certain microorganisms in oral flora and their metabolic substances constitute the primary extrinsic agents participating in the initiation of periodontal disease.
Recent periodontal ressearch has begun to elucidate the nature of the interaction between these bacterial substances and various host defense mechanisms. Bacterial toxins and antigens have been shown to activate the immune system of the host, causing tissue destruction and alveolar bone resorption, both which are characteristic of periodontal disease. .sup.1,2 FNT 1. Schluger S, Yuocelis NA, Page RC: Periodontal Disease. Philadelphia, Lea & Febiger, 1977. FNT 2. Page RC, Schroeder HE: Periodontitis in Man and Other Animals. Basel, Switzerland, Karger, 1982.
Also, studies have presented evidence that destruction of connective tissue and alveolar bone resorption are mediated by various proteases and protoglycanases released not only by the invading polymorphonuclear neutrophils and macrophages, but also, and more importantly, by most resident connective tissue cells, such as fibroblasts, osteoblasts, and others. .sup.3,4 FNT 3. Sellers A, Reynolds JJ, Meikle MC: Biochem J 171:493, 1978. FNT 4. Heath JK, et al. Biochem Biophys Acta 800:301-1984.
When confronted with the bacterial antigen, the inflammatory and noninflammatory cells of the host immune system respond by producing various lymphokines and cytokines, including inerleukin 1, which has been shown to be molecularly identical to osteoclast-activating factor (OAF).sup.5. These soluble mediators induce rapid synthesis of destructive enzymes by the host cells and thus appear to play a major role in modulating inflammatory responses. .sup.6 FNT 5. Dewhirst FE, et al., J. Immunol 135:2562-2568, 1985. FNT 6. Murphy G, Reynolds JJ; BioEssays 2: 55-60, 1985.
The primary manifestation of periodontal disease can be described as a hyper reaction of the host immune system. It is exquisitely indicated in clincal sutdies of patients with immunodeficiency diseases who demonstrate significantly lower levels of periodontal symptons in comparison with age-matched controls. Thus, the characterization of periodontal disease as a hypersensitivity reaction of the host defense mechanism, leading to the destruction of host tissue by host cells, has attracted the attention of many researchers in recent years.
Nevertheless, the preventive measures for periodontal disease have been focused primarily on physically or chemically eradicating bacterial plaque.
The increasing body of evidence suggests that bone resorption is a dynamic and complex chainlike event that invovles osteoclasts as well as various other cell types. .sup.7-9 Although anatomic resorption requires the simultaneous degradation of both mineral and organic matrices during cell-mediated resorption of living bone, the molecular details of this process have not been unraveled. Collagen is the major organic component of bone matrix, and collagenase is the enzyme principally associated with the degradation of collagen under physiologic conditions. This specific neutral protease has been associated with the breakdown of connective tissue in a variety of physiologic and pathologic tissues. FNT 7. Rodan GA, Rodan SB: Expression of the osteroblastic phenotype, In Peck Wa (ed): Bone and Mineral Research, Annual 2. Amsterdam, Elsevier, 1984, pp 244-285. FNT 8. Baron R, Vignery A, Horowitz M: Lymphocytes, macrophages and the regulation of bone remodeling. In Peck WA (ed.): Bone and Mineral Research, Annual 2 Amsterdam, Elsevier, 1984, pp 175-243. FNT 9. Chambers TJ; The pathobiology of the osteoclast. J Clin Pathol 38: 241-252, 1985.
It is an object of the invention to provide means for controlling alveolar bone resorption and limiting the levels of collagenase activity in advanced periodontal disease by orally adminstering certainspecified amounts of sanguinarine and its pseudoethanolate.